KRAS mutant protein inhibitors

ABSTRACT

The invention relates to a KRAS mutant protein inhibitors of formula (I), a composition containing the inhibitors and the use thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 17/218,568, filed Mar. 31, 2021, which is a continuation of Int'lAppl. No. PCT/CN2021/080995, filed Mar. 16, 2021, which claims priorityto Int'l Appl. No. PCT/CN2020/087943, filed Apr. 30, 2020, and Int'lAppl. No. PCT/CN2020/079667, filed Mar. 17, 2020, the disclosures ofeach of which are hereby incorporated by reference in their entireties.

TECHNICAL FIELD

The invention relates to a KRAS mutant protein inhibitors, a compositioncontaining the inhibitors and the use thereof.

BACKGROUND ART

RAS represents a population of 189 amino acid monomeric globularproteins (21 kDa molecular weight) that are associated with the plasmamembrane and bind to GDP or GTP, and RAS acts as a molecular switch.When the RAS contains bound GDP, it is in a stationary or closedposition and is “inactive”. When cells are exposed to certaingrowth-promoting stimuli, RAS is induced to exchange their bound GDP forGTP. In the case of binding to GTP, RAS is “opened” and is capable ofinteracting with other proteins (its “downstream targets”) andactivating the proteins. The RAS protein itself has an inherently lowability to hydrolyze GTP back to GDP, thereby turning itself into aclosed state. Closing RAS requires an exogenous protein called GTPaseactivating protein (GAP) that interacts with RAS and greatly acceleratesthe conversion of GTP to GDP. Any mutation in RAS that affects itsability to interact with GAP or convert GTP back to GDP will result inprolonged protein activation, and thus conduction to the cell to informits signaling of continued growth and division. Since these signalscause cell growth and division, over-activated RAS signaling canultimately lead to cancer.

Structurally, the RAS protein contains a G domain responsible for theenzymatic activity of RAS, guanine nucleotide binding and hydrolysis(GTPase reaction). It also contains a C-terminal extension called theCAAX cassette, which can be post-translationally modified andresponsible for targeting the protein to the membrane. The G domaincontains a phosphate binding ring (P-ring). The P-loop represents apocket of a binding nucleotide in a protein, and this is a rigid portionof a domain with conserved amino acid residues necessary for nucleotidebinding and hydrolysis (glycine 12 and lysine 16). The G domain alsocontains a so-called switch I region (residues 30-40) and a switch IIregion (residues 60-76), both of which are dynamic parts of the protein,since the dynamic portion is converted between stationary and loadedstates. The ability is often expressed as a “spring loaded” mechanism.The primary interaction is the hydrogen bond formed by threonine-35 andglycine-60 with the gamma-phosphate of GTP, which maintains the activeconformation of the switch 1 region and the switch 2 region,respectively. After hydrolysis of GTP and release of phosphate, the tworelax into an inactive GDP conformation.

The most notable members of the RAS subfamily are HRAS, KRAS and NRAS,which are primarily involved in many types of cancer. Mutation of any ofthe three major isoforms of the RAS gene (HRAS, NRAS or KRAS) is one ofthe most common events in human tumor formation. Approximately 30% ofall tumors in human tumors were found to carry some mutations in the RASgene. It is worth noting that KRAS mutations were detected in 25%-30% oftumors. In contrast, the rate of carcinogenic mutations in NRAS and HRASfamily members was much lower (8% and 3%, respectively). The most commonKRAS mutations were found at residues G12 and G13 in the P-loop as wellas at residue Q61.

G12C is a frequently occurring KRAS gene mutation (glycine-12 is mutatedto cysteine). This mutation has been found in about 13% of cancers,about 43% in lung cancer, and almost 100% in MYH-associated polyposis(familial colon cancer syndrome). However, targeting this gene withsmall molecules is a challenge.

Thus, despite advances in this field, there remains a need in the artfor improved compounds and methods for treating cancer, such as byinhibiting KRAS, HRAS or NRAS. The present invention fulfills this needand provides other related advantages.

SUMMARY OF INVENTION

In one aspect, provided herein is a compound of formula (I), astereoisomer thereof, an atropisomer thereof, a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable salt of thestereoisomer thereof or a pharmaceutically acceptable salt of theatropisomer thereof:

Wherein:

R₁₁, R₁₂, R₁₃, R₁₄ or R₁₅ is independently selected from halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3- 6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl, wherein, said —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, heteroC₂₋₆alkyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆,—C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆,—SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3- 6 memberedheterocyclic, —C₆₋₁₀aryl or 5-10 membered heteroaryl is independentlyoptionally substituted with one or more substituents selected fromhalogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₅, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl; said heterocyclic or heteroaryl at each occurrenceindependently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S,S═O or S(═O)₂;

R₂₁ or R₂₂ is independently selected from hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆,—NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic,3- 6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl,wherein, said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3- 6 membered heterocyclic, —C₆₋₁₀aryl or 5-10membered heteroaryl is independently optionally substituted with one ormore substituents selected from halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆,—S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3-6 membered heterocyclic,—C₆₋₁₀aryl, or 5-10 membered heteroaryl; said heterocyclic or heteroarylat each occurrence independently contains 1, 2, 3 or 4 heteroatomsselected from N, O, S, S═O or S(═O)₂;

R₃ is selected from —C₁₋₁₄alkyl, —C₂₋₁₄alkenyl, —C₂₋₁₄alkynyl,—C₆₋₁₀aryl, 5-10 membered heteroaryl, 3-14 membered heterocyclic,—C₃₋₁₄carbocyclic,

each ring C at each occurrence is independently selected from a C₃₋₁₄carbocyclic ring or a 3-14 membered heterocyclic ring, each ring D ateach occurrence is independently selected from a C₆₋₁₀ aryl ring or a5-10 membered heteroaryl ring, wherein, said —C₁₋₁₄alkyl, —C₂₋₁₄alkenyl,—C₂₋₁₄alkynyl, —C₆₋₁₀aryl, 5-10 membered heteroaryl, 3-14 memberedheterocyclic, —C₃₋₁₄carbocyclic,

is independently optionally substituted with 1R₃₁, 2R₃₁, 3R₃₁, 4R₃₁,5R₃₁ or 6R₃₁; said heterocyclic, heterocyclic ring, heteroaryl orheteroaryl ring at each occurrence independently contains 1, 2, 3 or 4heteroatoms selected from N, O, S, S═O or S(═O)₂;

Each R₃₁ at each occurrence is independently selected from halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3- 6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl, wherein, said —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, heteroC₂₋₆alkyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆,—C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆,—SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3- 6 memberedheterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl is independentlyoptionally substituted with one or more substituents selected fromhalogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3-6membered heterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl; saidheterocyclic or heteroaryl at each occurrence independently contains 1,2, 3 or 4 heteroatoms selected from N, O, S, S═O or S(═O)₂;

R₄ is selected from

Each G₁, G₂, G₃ or G₄ at each occurrence is independently selected fromN or CH;

Each n1, n2, n3, n4 or n5 at each occurrence is independently selectedfrom 0, 1, 2, 3, 4, 5 or 6, provided that n1 and n2 is not 0 at the sametime, n3 and n4 is not 0 at the same time;

Said

is independently optionally substituted with 1 R₄₂, 2 R₄₂, 3 R₄₂, 4 R₄₂,5 R₄₂ or 6 R₄₂;

Each R₄₁ at each occurrence is independently selected from

Each Q at each occurrence is independently selected from C(═O),NR₅C(═O), S(═O)₂ or NR₅S(═O)₂;

in

is selected from ═ or ≡;

when

is ═, R_(4a), R_(4b) or R_(4c) is independently selected from hydrogen,halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl, wherein, said —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, heteroC₂₋₆alkyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆,—C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆,—SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3-6 memberedheterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl is independentlyoptionally substituted with one or more substituents selected fromhalogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl; said heterocyclic or heteroaryl at each occurrenceindependently contains 1, 2, 3 or 4 heteroatom(s) selected from N, O, S,S═O or S(═O)₂; or

when

is ═, R_(4a) is selected from hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, —OC₁₋₆alkyl,—SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆,—NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic,3- 6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl,wherein, said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl,—CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3- 6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl is independently optionally substituted with one ormore substituents selected from halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆,—NR₅SO₂R₅, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3-6 memberedheterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl; and R_(4b) andR_(4c) together with the carbon to which they are both attached form aC₃₋₁₀ carbocyclic ring or a 3-10 membered heterocyclic ring, said C₃₋₁₀carbocyclic ring or said 3-10 membered heterocyclic ring is optionallysubstituted with one or more substituents selected from halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, oxo,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₅,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl; said heterocyclic, heterocyclic ring, heteroaryl orheteroaryl ring at each occurrence independently contains 1, 2, 3 or 4heteroatoms selected from N, O, S, S═O or S(═O)₂; or

when

is ═, R_(4a) and R_(4c) with the carbons to which they respectively areattached form a C₃₋₁₀ carbocyclic ring or a 3-10 membered heterocyclicring, said C₃₋₁₀ carbocyclic ring or said 3-10 membered heterocyclicring is optionally substituted with one or more substituents selectedfrom halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl,—CN, oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅,—OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆,—POR₅R₆, —C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or5-10 membered heteroaryl; and R_(4b) is selected from hydrogen, halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₅,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl, said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,heteroC₂₋₆alkyl, —CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅,—C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅,—S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3-6 membered heterocyclic,—C₆₋₁₀aryl, or 5-10 membered heteroaryl is independently optionallysubstituted with one or more substituents selected from halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, oxo,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆. —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl; said heterocyclic, heterocyclic ring, heteroaryl orheteroaryl ring at each occurrence independently contains 1, 2, 3 or 4heteroatoms selected from N, O, S, S═O or S(═O)₂;

-   -   when        is ≡, R_(4a) is absent, R_(4b) is absent, R_(4c) is selected        from hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        heteroC₂₋₆alkyl, —CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆,        —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆,        —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3-6        membered heterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl,        wherein, said —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        heteroC₂₋₆alkyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆. —C(═O)R₅,        —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆,        —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3-6 membered        heterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl is        independently optionally substituted with one or more        substituents selected from halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, oxo, —OC₁₋₆alkyl,        —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,        —C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆,        —POR₅R₆, —C₃₋₆carbocyclic, 3-6 membered heterocyclic,        —C₆₋₁₀aryl, or 5-10 membered heteroaryl; said heterocyclic or        heteroaryl at each occurrence independently contains 1, 2, 3 or        4 heteroatoms selected from N, O, S, S═O or S(═O)₂;

R_(4d) is halogen;

Each R₄₂ at each occurrence is independently selected from halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, oxo,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl, wherein, said —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆,—C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆,—SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆, —C₃₋₆carbocyclic, 3-6 memberedheterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl is independentlyoptionally substituted with one or more substituents selected fromhalogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅,—C(═O)NR₅R₆, —NR₅C(═O)R₆, —NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —POR₅R₆,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl;

Optionally, two R₄₂ together with the atom(s) to which they are both orrespectively attached form a C₃₋₆ carbocyclic or 3-6 memberedheterocyclic ring, said C₃₋₆ carbocyclic or said 3-6 memberedheterocyclic ring is independently optionally substituted with one ormore substituents selected from halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN, oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl,—NR₅R₆, —C(═O)R₅, —C(═O)OR₅, —OC(═O)R₅, —C(═O)NR₅R₆, —NR₅C(═O)R₅,—NR₅SO₂R₆, —SO₂R₅, —S(═O)₂NR₅R₆, —PO(R₅)₂, —C₃₋₆carbocyclic, 3-6membered heterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl; saidheterocyclic, heterocyclic ring, heteroaryl or heteroaryl ring at eachoccurrence independently contains 1, 2, 3 or 4 heteroatoms selected fromN, O, S, S═O or S(═O)₂;

Each R₅ or R₆ at each occurrence is independently selected from hydrogenor —C₁₋₆alkyl; or

R₅ and R₆ together with the atom(s) to which they are both orrespectively attached form a 3-10 membered heterocyclic ring, said 3-10membered heterocyclic ring is optionally further contains 1, 2, 3 or 4heteroatoms selected from N, O, S, S(═O) or S(═O)₂, and said 3-10membered heterocyclic ring is independently optionally substituted with1 R₅₁, 2 R₅₁, 3 R₅₁, 4 R₅₁, 5 R₅₁ or 6 R₅₁;

Each R₅₁ at each occurrence is independently selected from halogen,—C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,—OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₇R₈, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,—C(═O)NR₇R₈, —NR₇C(═O)R₈, —NR₇SO₂R₈, —SO₂R₇, —S(═O)₂NR₇R₈, —POR₇R₈,—C₃₋₆carbocyclic, 3- 6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl, wherein, said —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, heteroC₂₋₆alkyl, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₇R₈,—C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇, —C(═O)NR₇R₈, —NR₇C(═O)R₈, —NR₇SO₂R₈,—SO₂R₇, —S(═O)₂NR₇R₈, —POR₇R₈, —C₃₋₆carbocyclic, 3- 6 memberedheterocyclic, —C₆₋₁₀aryl, or 5-10 membered heteroaryl is independentlyoptionally substituted with one or more substituents selected fromhalogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, heteroC₂₋₆alkyl, —CN,oxo, —OC₁₋₆alkyl, —SC₁₋₆alkyl, —NR₇R₈, —C(═O)R₇, —C(═O)OR₇, —OC(═O)R₇,—C(═O)NR₇R₈, —NR₇C(═O)R₈, —NR₇SO₂R₈, —SO₂R₇, —S(═O)₂NR₇R₈, —POR₇R₈,—C₃₋₆carbocyclic, 3-6 membered heterocyclic, —C₆₋₁₀aryl, or 5-10membered heteroaryl; said heterocyclic or heteroaryl at each occurrenceindependently contains 1, 2, 3 or 4 heteroatoms selected from N, O, S,S═O or S(═O)₂;

Each R₇ or R₈ at each occurrence is independently selected from hydrogenor —C₁₋₆alkyl.

In some embodiments, provided herein is a compound of formula (I), astereoisomer thereof, an atropisomer thereof, a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable salt of thestereoisomer thereof or a pharmaceutically acceptable salt of theatropisomer thereof:

Wherein:

R₁₁, R₁₂, R₁₃, R₁₄ or R₁₅ is independently selected from —OH; halogen;—NR_(a)R_(b); —C₁₋₆alkyl; —OC₁₋₆alkyl; —C₁₋₆alkylene-OH;—C₁₋₆alkylene-O—C₁₋₆alkyl; —C₁₋₆alkyl substituted with halogen, —NH₂,—CN or —OH; —O—C₁₋₆alkyl substituted with halogen, —NH₂, —CN or —OH;—SO₂R_(a); —CN; —C(═O)NR_(a)R_(b); —C(═O)R_(a); —OC(═O)R_(a);—C(═O)OR_(a); or —C₃₋₆carbocyclic;

R_(a) or R_(b) is independently selected from hydrogen or —C₁₋₆alkyl;

R₂₁ is selected from hydrogen; halogen; —C₁₋₆alkyl; —C₁₋₆alkylsubstituted with halogen, —NH₂, —CN or —OH; —C₂₋₆alkenyl; or—C₃₋₆carbocyclic;

R₂₂ is selected from hydrogen; halogen; —C₁₋₆alkyl; —C₁₋₆alkylsubstituted with halogen, —NH₂, —CN or —OH; —C₂₋₆alkenyl; or—C₃₋₆carbocyclic;

R₃ is selected from —C₆₋₁₀aryl or 5-10 membered heteroaryl, each of 5-10membered heteroaryl at each occurrence independently contains 1, 2, 3 or4 heteroatoms selected from N, O or S, each of —C₆₋₁₀aryl or 5-10membered heteroaryl at each occurrence is independently optionallysubstituted with 1 R₃₁, 2 R₃₁, 3 R₃₁, 4 R₃₁, 5 R₃₁ or 6 R₃₁;

Each of R₃₁ at each occurrence is independently selected from halogen,—C₁₋₆alkyl, —CN, —OH, —O—C₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂or —C₃₋₆carbocyclic;

R₄ is selected from

is independently optionally substituted with 1 R₄₂, 2 R₄₂, 3 R₄₂, 4 R₄₂,5 R₄₂ or 6 R₄₂;

n1 or n2 is independently selected from 1, 2, 3, 4, 5 or 6;

R₄₁ is selected from

R_(4a), R_(4b) or R_(4c) is independently selected from hydrogen,halogen, —C₁₋₆alkyl or —C₁₋₆alkylene-N(C₁₋₆alkyl)₂; Each of R₄₂ at eachoccurrence is independently selected from —C₁₋₆alkyl; —C₁₋₆alkylene-CNor —C₁₋₆alkyl substituted with halogen.

In some embodiments, R₁₁, R₁₂, R₁₃, R₁₄ or R₁₅ is independently selectedfrom —OH; —F; —Cl; —Br; —NR_(a)R_(b); —C₁₋₃alkyl; —OC₁₋₃alkyl;—C₁₋₃alkylene-OH; —C₁₋₃alkylene-O—C₁₋₃alkyl; —C₁₋₃alkyl substituted with—F or —Cl; —O—C₁₋₃alkyl substituted with —F or —Cl; —SO₂R_(a); —CN;—C(═O)NR_(a)R_(b); —C(═O)R_(a); —OC(═O)R_(a); —C(═O)OR_(a); 3-memberedcarbocyclic; 4-membered carbocyclic; 5-membered carbocyclic or6-membered carbocyclic;

R_(a) or R_(b) is independently selected from hydrogen or —C₁₋₃alkyl.

In some embodiments, R₁₁, R₁₂, R₁₃, R₁₄ or R₁₅ is independently selectedfrom —OH, —F, —Cl, —NH₂, —NHCH₃, —N(CH₃)₂, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, —CH₂OH, —CH₂CH₂OH,—CH₂OCH₃, —CHF₂, —CH₂F, —CF₃, —OCH₂F, —OCHF₂, —OCF₃, —SO₂CH₃, —CN,—C(═O)NH₂, —C(═O)CH₃, —OC(═O)CH₃, —C(═O)OCH₃ or 3-membered carbocyclic.

In some embodiments, R₁₁, R₁₂, R₁₃, R₁₄ or R₁₅ is independently selectedfrom —OH, —F, —Cl, —NH₂, —CH₃ or —CF₃.

In some embodiments, R₁₁ is selected from —OH or —NH₂; and R₁₂, R₁₃, R₁₄or R₁₅ is independently selected from —F or —Cl.

In some embodiments, R₁ is selected from:

In some embodiments, R₂₁ is selected from hydrogen; —F; —Cl; —Br;—C₁₋₃alkyl; —C₁₋₃alkyl substituted with —F or —Cl; —C₂₋₃alkenyl; or—C₃₋₆carbocyclic.

In some embodiments, R₂₁ is selected from hydrogen; —F; —Cl; methyl;ethyl; propyl; isopropyl; methyl substituted with —F; ethyl substitutedwith —F; propyl substituted with —F; isopropyl substituted with —F;ethenyl; propenyl; 3 membered carbocyclic; 4 membered carbocyclic; 5membered carbocyclic; or 6 membered carbocyclic.

In some embodiments, R₂₁ is selected from —F or —Cl.

In some embodiments, R₂₁ is selected from —F.

In some embodiments, R₂₂ is selected from hydrogen; —F; —Cl; —Br;—C₁₋₃alkyl; —C₁₋₃alkyl substituted with —F or —Cl; —C₂₋₃alkenyl; or—C₃₋₆carbocyclic.

In some embodiments, R₂₂ is selected from hydrogen; —F; —Cl; methyl;ethyl; propyl; isopropyl; methyl substituted with —F; ethyl substitutedwith —F; propyl substituted with —F; isopropyl substituted with —F;ethenyl; propenyl; 3 membered carbocyclic; 4 membered carbocyclic; 5membered carbocyclic; or 6 membered carbocyclic.

In some embodiments, R₂₂ is hydrogen.

In some embodiments, R₃ is selected from phenyl, naphthyl, 5 memberedheteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 memberedheteroaryl, 9 membered heteroaryl or 10 membered heteroaryl, saidheteroaryl at each occurrence independently contains 1, 2 or 3heteroatoms selected from N or O, said phenyl, naphthyl, 5 memberedheteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 memberedheteroaryl, 9 membered heteroaryl or 10 membered heteroaryl isindependently optionally substituted by 1 R₃₁, 2 R₃₁, 3 R₃₁, 4 R₃₁ or 5R₃₁.

In some embodiments, R₃ is selected from phenyl or 6 memberedheteroaryl, said heteroaryl contains 1 or 2 heteroatoms selected from N,said phenyl or 6 membered heteroaryl at each occurrence is independentlyoptionally substituted with 1 R₃₁, 2 R₃₁, 3 R₃₁ or 4 R₃₁.

In some embodiments, R₃ is selected from

at each occurrence is independently optionally substituted with 1 R₃₁, 2R₃₁, 3 R₃₁ or 4 R₃₁.

In some embodiments, each R₃₁ at each occurrence is independentlyselected from —F, —Cl, —Br, —C₁₋₃alkyl, —CN, —OH, —O—C₁₋₃alkyl, —NH₂,—NH(C₁₋₃alkyl), —N(C₁₋₃alkyl)₂ or —C₃₋₆carbocyclic.

In some embodiments, each R₃₁ at each occurrence is independentlyselected from —F, —Cl, methyl, ethyl, propyl, isopropyl, —CN, —OH,methoxy, ethoxy, propoxy, isopropoxy, —NH₂, —NHCH₃, —NHCH₂CH₃,—NH(CH₂CH₂CH₃), —NH(CH(CH₃)₂), —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)(CH₂CH₃), 3membered carbocyclic, 4 membered carbocyclic, 5 membered carbocyclic or6 membered carbocyclic.

In some embodiments, each R₃₁ at each occurrence is independentlyselected from methyl or isopropyl.

In some embodiments, R₃ is selected from

In some embodiments, R₃ is

In some embodiments, R₄ is selected from

is independently optionally substituted by 1 R₄₂, 2 R₄₂, 3 R₄₂ or 4 R₄₂;IDC-37 Cl

n1 is selected from 1, 2 or 3;

n2 is selected from 1, 2 or 3.

In some embodiments, R₄ is selected from

is independently optionally substituted with 1 R₄₂ or 2 R₄₂;

n1 is selected from 1 or 2;

-   -   n2 is selected from 1 or 2.

In some embodiments, R₄ is selected from

is independently optionally substituted by 1 R₄₂ or 2 R₄₂.

In some embodiments, R₄₁ is selected from

R_(4a), R_(4b), or R_(4c) is independently selected from hydrogen, —F,—Cl, —Br, —C₁₋₃alkyl or —C₁₋₃alkylene-N(C₁₋₃alkyl)₂.

In some embodiments, R_(4a), R_(4b) or R_(4c) is independently selectedfrom hydrogen, —F, —Cl, methyl, ethyl, propyl, isopropyl, —CH₂—N(CH₃)₂,—CH₂—N(CH₂CH₃)₂ or —CH₂—N(CH₃)(CH₂CH₃).

In some embodiments, R_(4a), R_(4b) or R_(4c) is independently selectedfrom hydrogen, —F, methyl or —CH₂—N(CH₃)₂.

In some embodiments, R_(4a) is selected from hydrogen or —F;

R_(4b) is hydrogen;

R_(4c) is selected from hydrogen or —CH₂—N(CH₃)₂.

In some embodiments, R₄₁ is independently selected from:

In some embodiments, R₄ is selected from

at each occurrence is independently optionally substituted with 1 R₄₂ or2 R₄₂.

In some embodiments, each R₄₂ at each occurrence is independentlyselected from —C₁₋₃alkyl; —C₁₋₃alkylene-CN; or —C₁₋₃alkyl substitutedwith —F or —Cl.

In some embodiments, each R₄₂ at each occurrence is independentlyselected from methyl; ethyl; propyl; isopropyl; -methylene-CN;-ethylene-CN; -propylene-CN; methyl substituted with —F; ethylsubstituted with —F; propyl substituted with —F; or isopropylsubstituted with —F.

In some embodiments, each R₄₂ at each occurrence is independentlyselected from methyl; ethyl; -methylene-CN or methyl substituted with—F.

In some embodiments, each R₄₂ at each occurrence is independentlyselected from —CH₃, —CH₂CH₃, —CH₂CN, —CHF₂ or —CF₃.

In some embodiments, R₄ is selected from:

In some embodiments, R₄ is selected from:

In some embodiments, R₄ is selected from:

In some embodiments, the compound is selected from:

In another aspect, provided herein is a method for preparing thecompound of formula (I), the stereoisomer thereof, the atropisomerthereof, the pharmaceutically acceptable salt thereof, thepharmaceutically acceptable salt of the stereoisomer thereof or thepharmaceutically acceptable salt of the atropisomer thereof, the methodcomprises a coupling reaction between a compound of formula (II) and acompound of formula(III) according to the following reaction Scheme 1 orbetween a compound of formula (II′) and a compound of formula(III′)according to the following reaction Scheme 2 catalyzed by a transitionmetal palladium or nickel reagent:

Wherein:

the L in the compound of formula(III) or formula(H′) is a leaving group;preferably, the leaving group is selected from halogen, —OS(O)₂CF₃ or-OTs; more preferably, the halogen is selected from —F, —Cl, —Br, or —I;more preferably, the leaving group is —Cl or —Br;

the X in the compound of formula (II) or formula(III′) is selected fromboronic acid, borate ester or organotin; more preferably, the X isselected from

Preferably, the coupling reaction is Suzuki coupling reaction or Stillecoupling reaction;

Preferably, the coupling reaction is catalyzed by the transition metalpalladium reagent; more preferably, the transition metal palladiumreagent is Pd(PPh₃)₄.

In another aspect, provided herein is an intermediate of formula (IV), astereoisomer thereof, an atropisomer thereof, a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable salt of thestereoisomer thereof or a pharmaceutically acceptable salt of theatropisomer thereof:

Wherein:

R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₂₁, R₂₂ or R₃ is defined as in the presentinvention; and R₄′ is selected from

Each G₁′, G₂′, G₃′ or G₄′ at each occurrence is independently selectedfrom NH or CH;

Each n6, n7, n8, n9 or n10 at each occurrence is independently selectedfrom 0, 1, 2, 3, 4, 5 or 6, provided that n6 and n7 is not 0 at the sametime, n8 and n9 is not 0 at the same time;

Said

is independently optionally substituted with 1 R₄₂, 2 R₄₂, 3 R₄₂, 4 R₄₂,5 R₄₂ or 6 R₄₂;

Each R₄₂ is defined as in the present invention.

In some embodiments, the intermediate of formula (IV) is the formula(IV′):

n6 or n7 is selected from 1, or 2; and s is selected from 0, 1, 2, or 3;

R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₂₁, R₂₂, R₃ or R₄₂ is defined as in thepresent invention.

In some embodiments, the intermediate of formula (IV) is selected from:

In another aspect, provided herein is a method for preparing thecompound of formula (I′), the stereoisomer thereof, the atropisomerthereof, the pharmaceutically acceptable salt thereof, thepharmaceutically acceptable salt of the stereoisomer thereof or thepharmaceutically acceptable salt of the atropisomer thereof of thepresent invention, the method comprises a reaction between anintermediate of formula (IV′) and a compound of formula(V′) according tothe following reaction Scheme 3 under a basic condition:

Wherein:

the L₂ in the compound of formula(V′) is a leaving group; preferably,the leaving group is selected from halogen, —OS(O)₂CF₃ or -OTs; morepreferably, the halogen is selected from —F, —Cl, —Br, or —I; morepreferably, the leaving group is —Cl or —Br;

R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₂₁, R₂₂, R₃, R₄₂, n₆, n₇ or s in the formula(IV′) or formula (I′) is defined as in the present invention; andR_(4a), R_(4b) or R_(4c) in formula (IV′) is defined as in the presentinvention; preferably, R_(4a), R_(4b) or R_(4c) is hydrogen.

In another aspect, provided herein is a pharmaceutical compositioncomprising the compound of formula (I), the stereoisomer thereof, theatropisomer thereof, the pharmaceutically acceptable salt thereof, thepharmaceutically acceptable salt of the stereoisomer thereof or thepharmaceutically acceptable salt of the atropisomer thereof of thepresent invention, and at least one pharmaceutically acceptableexcipient.

In some embodiments, the said compound in a weight ratio to the saidexcipient within the range from about 0.0001 to about 10. In someembodiments, the said compound in a weight ratio to the said excipientwithin the range from about 0.01 to about 0.8. In some embodiments, thesaid compound in a weight ratio to the said excipient within the rangefrom about 0.02 to about 0.2. In some embodiments, the said compound ina weight ratio to the said excipient within the range from about 0.05 toabout 0.15.

In another aspect, provided herein is use of the compound of formula(I), the stereoisomer thereof, the atropisomer thereof, thepharmaceutically acceptable salt thereof, the pharmaceuticallyacceptable salt of the stereoisomer thereof or the pharmaceuticallyacceptable salt of the atropisomer thereof of the present invention orthe pharmaceutical composition of the present invention for themanufacture of a medicament for the treatment of cancer related to KRASG12C mutant protein. In some embodiments, the cancer is selected fromblood cancer, pancreatic cancer, colon cancer, rectal cancer, colorectalcancer or lung cancer. In some embodiments, the blood cancer is selectedfrom acute myeloid leukemia or acute lymphocytic leukemia; the lungcancer is selected from non-small cell lung cancer or small cell lungcancer.

In another aspect, there is provided that a method of treating a subjecthaving cancer related to KRAS G12C mutant protein, said methodcomprising administering to the subject a therapeutically effectiveamount of the compound of formula (I), the stereoisomer thereof, theatropisomer thereof, the pharmaceutically acceptable salt thereof, thepharmaceutically acceptable salt of the stereoisomer thereof or thepharmaceutically acceptable salt of the atropisomer thereof of thepresent invention; or the pharmaceutical composition of the presentinvention. In some embodiments, the cancer is selected from bloodcancer, pancreatic cancer, colon cancer, rectal cancer, colorectalcancer or lung cancer. In some embodiments, the blood cancer is selectedfrom acute myeloid leukemia or acute lymphocytic leukemia; the lungcancer is selected from non-small cell lung cancer or small cell lungcancer.

In another aspect, provided herein is a compound of formula (I), astereoisomer thereof, an atropisomer thereof, a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable salt of thestereoisomer thereof or a pharmaceutically acceptable salt of theatropisomer thereof of the present invention; or the pharmaceuticalcomposition of the present invention for use in the treatment of cancerrelated into KRAS G12C mutant protein. In some embodiments, the canceris selected from blood cancer, pancreatic cancer, colon cancer, rectalcancer, colorectal cancer or lung cancer. In some embodiments, the bloodcancer is selected from acute myeloid leukemia or acute lymphocyticleukemia; the lung cancer is selected from non-small cell lung cancer orsmall cell lung cancer.

Definition

The term “halogen” or “halo”, as used herein, unless otherwiseindicated, means fluoro, chloro, bromo or iodo. The preferred halogengroups include —F, —Cl and —Br. The more preferred halogen groupsinclude —F and —Cl.

The term “alkyl”, as used herein, unless otherwise indicated, includessaturated monovalent hydrocarbon radicals having straight or branched.For example, alkyl radicals include methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl,2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branchedarrangement.

The term “alkylene” means a difunctional group obtained by removal of ahydrogen atom from an alkyl group that is defined above. For example,methylene (i.e., —CH₂—), ethylene (i.e., —CH₂—CH₂— or —CH(CH₃)—) andpropylene (i.e., —CH₂—CH₂, —CH₂—, —CH(—CH₂—CH₃)— or —CH₂—CH(CH₃)—).

The term “alkenyl” means a straight or branch-chained hydrocarbonradical containing one or more double bonds and typically from 2 to 20carbon atoms in length. For example, “C₂₋₆alkenyl” contains from 2 to 6carbon atoms. Alkenyl group include, but are not limited to, forexample, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl,octenyl and the like.

The term “alkynyl” contains a straight or branch-chained hydrocarbonradical containing one or more triple bonds and typically from 2 to 20carbon atoms in length. For example, “C₂₋₆alkynyl” contains from 2 to 6carbon atoms. Representative alkynyl groups include, but are not limitedto, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl andthe like.

The term “alkoxy” radicals are oxygen ethers formed from the previouslydescribed alkyl groups.

The term “aryl” or “aryl ring”, as used herein, unless otherwiseindicated, refers to an unsubstituted or substituted mono or polycyclicaromatic ring system only containing carbon ring atoms. The preferredaryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems.Phenyl and naphthyl are preferred aryls.

The term “heterocyclic” or “heterocyclic ring”, as used herein, unlessotherwise indicated, refers to unsubstituted and substituted mono orpolycyclic non-aromatic ring system containing one or more ringheteroatom(s), which comprising monocyclic heterocyclic (ring), bicyclicheterocyclic (ring), bridged heterocyclic (ring), fused heterocyclic(ring) or spiro heterocyclic (ring). Preferred heteroatoms include N, O,and S, including N-oxides, sulfur oxides, and dioxides. Preferably theheterocyclic (ring) is three to ten membered and is either fullysaturated or has one or more degrees of unsaturation. Multiple degreesof substitution, preferably one, two or three, are included within thepresent definition of heterocyclic (ring). Examples of such heterocyclicgroups include, but are not limited to azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl,azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl,tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone andoxadiazolyl.

The term “heteroaryl” or “heteroaryl ring”, as used herein, unlessotherwise indicated, represents an aromatic ring system containingcarbon(s) and at least one heteroatom. Heteroaryl or heteroaryl ring maybe monocyclic or polycyclic, substituted or unsubstituted. A monocyclicheteroaryl group may have 1 to 4 heteroatoms in the ring, while apolycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclicheteroaryl ring may contain fused, spiro or bridged ring junction, forexample, bycyclic heteroaryl is a polycyclic heteroaryl. Bicyclicheteroaryl rings may contain from 8 to 12 member atoms. Monocyclicheteroaryl rings may contain from 5 to 8 member atoms (cabons andheteroatoms). Examples of heteroaryl groups include, but are not limitedto thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl,indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl,benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl,benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinylor isoquinolinyl.

The term “carbocyclic” or “carbocyclic ring” refers to a substituted orunsubstituted monocyclic ring, bicyclic ring, bridged ring, fused ring,sipiro ring non-aromatic ring system only containing carbon atoms.

The carbocyclic (ring) contain cycloalkyl without substituted degreesand carbocyclic with one or more substituted degrees. Examplary“cycloalkyl” groups includes but not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and so on.

The term “oxo” refers to oxygen atom together with the attached carbonatom forms the group

The term “—C₁₋₆alkylene-N(C₁₋₆alkyl)₂” refers to the —C₁₋₆alkyl asdefined above substituted by —N(C₁₋₆alkyl)₂.

The term “—C₁₋₆alkylene-CN” refers to the —C₁₋₆alkyl as defined abovesubstituted by —CN.

The term “heteroalkyl” refers to the presence of heteroatoms between anytwo carbon atoms in the alkyl group as defined above, such as N or Oatoms. For example, “heteroC₂₋₆alkyl” means that there are N atom or Oatom between any two carbon atoms in the C₂₋₆ alkyl group, including butnot limited to —CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂NHCH₃, or —CH₂N(CH₃)₂ and thelike.

The term “composition”, as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.Accordingly, pharmaceutical compositions containing the compounds of thepresent invention as the active ingredient as well as methods ofpreparing the instant compounds are also part of the present invention.

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salt(s). For use in medicine, the saltsof the compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salt(s)”. The pharmaceutically acceptable salt forms includepharmaceutically acceptable acidic/anionic or basic/cationic salts. Thepharmaceutically acceptable acidic/anionic salt generally takes a formin which the basic nitrogen is protonated with an inorganic or organicacid.

The present invention includes within its scope the prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds that are readily converted invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the subject. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniques knowin the art as well as those methods set forth herein.

The present invention includes compounds described can contain one ormore asymmetric centers and may thus give rise to diastereomers andoptical isomers. The present invention includes all such possiblediastereomers as well as their racemic mixtures, their substantiallypure resolved enantiomers, all possible geometric isomers, andpharmaceutically acceptable salts thereof.

The present invention includes all stereoisomers of the compound andpharmaceutically acceptable salts thereof. Further, mixtures ofstereoisomers as well as isolated specific stereoisomers are alsoincluded. During the course of the synthetic procedures used to preparesuch compounds or in using racemization or epimerization proceduresknown to those skilled in the art, the products of such procedures canbe a mixture of stereoisomers.

The term “stereoisomer” as used in the present invention refers to anisomer in which atoms or groups of atoms in the molecule are connectedto each other in the same order but differ in spatial arrangement,including conformational isomers and conformational isomers. Theconfiguration isomers include geometric isomers and optical isomers, andoptical isomers mainly include enantiomers and diastereomers. Theinvention includes all possible stereoisomers of the compound.

Certain of the compounds provided herein may exist as atropisomers,which are conformational stereoisomers that occur when rotation about asingle bond in the molecule is prevented, or greatly slowed, as a resultof steric interactions with other pails of the molecule. The compoundsprovided herein include all atropisomers, both as pure individualatropisomer preparations, enriched preparations of each, or anon-specific mixture of each. Where the rotational barrier about thesingle bond is high enough, and interconversion between conformations isslow enough, separation and isolation of the isomeric species may bepermitted.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. The isotopes of hydrogen can be denoted as ¹H(hydrogen),²H(deuterium) and ³H(tritium). They are also commonly denoted as D fordeuterium and T for tritium. In the application, CD₃ denotes a methylgroup wherein all of the hydrogen atoms are deuterium. Isotopes ofcarbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of theinvention can generally be prepared by conventional techniques known tothose skilled in the art or by processes analogous to those describedherein, using an appropriate isotopically-labeled reagent in place ofthe non-labeled reagent.

When a tautomer of the compound exists, the present invention includesany possible tautomers and pharmaceutically acceptable salts thereof,and mixtures thereof, except where specifically stated otherwise.

The pharmaceutical compositions of the present invention comprise thecompound (or the stereoisomer, the astropisomer thereof, thepharmaceutically acceptable salt thereof, the pharmaceuticallyacceptable salt of the stereoisomer, or the pharmaceutically acceptablesalt of the astropisomer) as an active ingredient, and apharmaceutically acceptable carrier and optionally other adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In practice, the compounds or a prodrug or a metabolite orpharmaceutically acceptable salts thereof, of this invention can becombined as the active ingredient in intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.oral or parenteral (including intravenous). Thus, the pharmaceuticalcompositions of the present invention can be presented as discrete unitssuitable for oral administration such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.Further, the compositions can be presented as a powder, as granules, asa solution, as a suspension in an aqueous liquid, as a non-aqueousliquid, as an oil-in-water emulsion or as a water-in-oil liquidemulsion. In addition to the common dosage forms set out above, thecompound or a pharmaceutically acceptable salt thereof, may also beadministered by controlled release means and/or delivery devices. Thecompositions may be prepared by any of the methods of pharmacy. Ingeneral, such methods include a step of bringing into association theactive ingredient with the carrier that constitutes one or morenecessary ingredients. In general, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers or finely divided solid carriers or both. The product can thenbe conveniently shaped into the desired presentation.

The pharmaceutical carrier/excipient employed can be, for example, asolid, liquid or gas. Examples of solid carriers include lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,and stearic acid. Examples of liquid carriers are sugar syrup, peanutoil, olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen. In preparing the compositions for oral dosageform, any convenient pharmaceutical media may be employed. For example,water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like may be used to form oral liquidpreparations such as suspensions, elixirs and solutions; while carrierssuch as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents, and thelike may be used to form oral solid preparations such as powders,capsules and tablets. Because of their ease of administration, tabletsand capsules are the preferred oral dosage units whereby solidpharmaceutical carriers are employed. Optionally, tablets may be coatedby standard aqueous or nonaqueous techniques.

A tablet containing the composition of this invention may be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets may be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets may be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent. Eachtablet preferably contains from about 0.05 mg to about 5 g of the activeingredient and each cachet or capsule preferably containing from about0.05 mg to about 5 g of the active ingredient. For example, aformulation intended for the oral administration to humans may containfrom about 0.5 mg to about 5 g of active agent, compounded with anappropriate and convenient amount of carrier material which may varyfrom about 0.05 to about 95 percent of the total composition.

Unit dosage forms will generally contain between from about 0.01 mg toabout 2 g of the active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or2000 mg.

Pharmaceutical compositions of the present invention suitable forparenteral administration may be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropyl cellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder or the like. Further, the compositionscan be in a form suitable for use in transdermal devices. Theseformulations may be prepared, utilizing a compound of this invention ora pharmaceutically acceptable salt thereof, via conventional processingmethods. As an example, a cream or ointment is prepared by admixinghydrophilic material and water, together with about 0.05 wt % to about10 wt % of the compound, to produce a cream or ointment having a desiredconsistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories may be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above may include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including antioxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound or pharmaceutically acceptable salts thereof, mayalso be prepared in powder or liquid concentrate form.

Generally, dosage levels on the order of from about 0.001 mg/kg to about150 mg/kg of body weight per day are useful in the treatment of theabove-indicated conditions or alternatively about 0.05 mg to about 7 gper patient per day. For example, inflammation, cancer, psoriasis,allergy/asthma, disease and conditions of the immune system, disease andconditions of the central nervous system (CNS), may be effectivelytreated by the administration of from about 0.001 to 50 mg of thecompound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5 g per patient per day.

It is understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theage, body weight, general health, sex, diet, time of administration,route of administration, rate of excretion, drug combination and theseverity of the particular disease undergoing therapy.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is the graph of tumor volume varying with the days after tumorimplantation after administration of Compound 2-1 or vehicle inNCI-H1373 (KRAS^(G12C)) xenograft model.

FIG. 2 is the graph of body weight varying with the days after tumorimplantation after administration of compound 2-1 or vehicle in SW837(KRAS^(G12C)) xenograft model.

EXAMPLES

Compounds of the present invention can be synthesized from commerciallyavailable reagents using the synthetic methods described herein. Theexamples which outline specific synthetic route below are meant toprovide guidance to the ordinarily skilled synthetic chemist, who willreadily appreciate that the solvent, concentration, reagent, protectinggroup, order of synthetic steps, time, temperature, and the like can bemodified as necessary, well within the skill and judgment of theordinarily skilled artisan.

The following Examples are provided to better illustrate the presentinvention. All parts and percentages are by weight and all temperaturesare degrees Celsius, unless explicitly stated otherwise. The followingabbreviations in Table 1 have been used in the examples:

TABLE 1 MeOH Methanol EtOH Ethanol DCM Dichloromethane TEA TriethylamineTFA Trifluoroacetic acid DMF N,N-Dimethylformamide DMA N,N-dimethylacetamide THF Tetrahydrofuran MeCN/ACN Acetonitrile HATU2-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride HOBT 1-Hydroxybenzotriazole LiHMDS LithiumHexamethyldisilazide Hunig's base/ N,N-Diisopropylethylamine DIEA/DIPEAEA Ethyl acetate min Minute(s) h Hour(s) Pre-TLC Preparative thin layerchromatography prep-HPLC Preparative High Performance LiquidChromatography SFC Supercritical fluid chromatography Pd(dppf)Cl₂ [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) R.T./r.t./RT Roomtemperature(20° C.~30° C.) AcOH Acetic acid Pd(PPh₃)₄Tetrakis(triphenylphosphine)palladium NCS N-Chlorosuccinimide Hexn-Hexane PPTS Pyridinium 4-toluenesulfonate IPA Isopropanol DHP3,4-Dihydro-2H-pyran a.q./aq Aqueous AcOK/KOAc Potassium acetate NMPMethyl-2-pyrrolidinone

Example 14-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1);(M)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;and(P)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Step 1.2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide

Into a 500-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed2,6-dichloro-5-fluoronicotinic acid (25.218 g, 120.09 mmol) and SOCl₂(100 mL).

The mixture was stirred at 80° C. for 2 h. The reaction was cooled toroom temperature and concentrated under vacuum. The mixture was dilutedby CH₃CN (20 mL), this was followed by the addition of NH₃.H₂O (100 mL)in dropwise at 0° C. The mixture was stirred at RT for 1 h. The solidwas collected by filtration to give 25.101 g (crude) of2,6-dichloro-5-fluoronicotinamide which was used directly in the nextstep.

Into a 500-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed2,6-dichloro-5-fluoronicotinamide (25.101 g, crude) and THF (200 mL).This was followed by the addition of oxalyl chloride (21.884 g, 172.42mmol) in dropwise. The mixture was stirred at 80° C. for 2 h. Theresulting solution was concentrated under vacuum. This was followed bythe addition of 2-isopropyl-4-methylpyridin-3-amine (19.830 g, 132.11mmol) at 0° C. The mixture was stirred at RT for 1 h. The reaction wasthen quenched by the addition of water (200 mL). The resulting solutionwas extracted with dichloromethane (3×200 mL). The organic layers werecombined and washed with brine (200 mL), dried over anhydrous Na₂SO₄.The residue was concentrated under vacuum and applied onto a silica gelcolumn eluted with EA/hexane (v/v=1:2). This resulted in 42.01 g (91%)of2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamideas red oil. LCMS: m/z=385 [M+1]⁺.

Step 2.7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Into a 500-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed2,6-dichloro-5-fluoro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide (42.01 g, 109.83 mmol), THF (200 mL) and stirred at roomtemperature. NaH (9.493 g, 237.33 mmol) was added at −10° C. The mixturewas stirred at RT for 2 h. The reaction was poured into water (200 mL).The resulting solution was extracted with dichloromethane (3×100 mL).The organic layers were combined and washed with brine (100 mL), driedover anhydrous Na₂SO₄. The residue was concentrated under vacuum andapplied onto a silica gel column eluted with EA/hexane (v/v=61/4). Thisresulted in 25.11 g (65%) of7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneas red oil. LCMS: m z=349 [M+1]⁺.

Step 3. tert-butyl(S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Into a 500-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione(25.074 g, 74.96 mmol), acetonitrile (200 mL), POCl₃ (45.97 g, 299.81mmol) and DIEA (58.12 g, 449.70 mmol). The mixture was stirred at 80° C.for 2 h. The reaction was cooled to room temperature and concentratedunder vacuum. This resulted in4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(30 g, crude) which was used directly in the next step.

Into a 500-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(30 g, crude), acetonitrile (200 mL), DIEA (58.12 g, 449.70 mmol) andtert-butyl (S)-3-methylpiperazine-1-carboxylate (15.801 g, 78.90 mmol).The reaction mixture was stirred for 2 h at room temperature. Thereaction was then quenched by the addition of water (500 mL). Theresulting solution was extracted with ethyl acetate (3×500 mL). Theorganic layers were combined and washed with brine (500 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel column eluted with EA/hexane (v/v=4/1). Thisresulted in 15.18 g (38.14% in two steps) of tert-butyl(S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylateas yellow solid. LCMS: m z=531 [M+1]⁺.

Step 4.(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Into a 250-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed tert-butyl(S)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(14.708 g, 27.698 mmol), DCM (20 mL) and TFA (4 ml). The reactionmixture was stirred at room temperature for 2 h. The reaction mixturewas concentrated under vacuum. The residue was dissolved by DCM (20 mL)in a 250-mL round-bottom flask. This was followed by the addition ofDIEA (4 mL). The reaction mixture was cooled to 0° C. and acryloylchloride (6.756 g, 74.65 mmol) was added. The mixture stirred at roomtemperature for 1 h. The reaction was then quenched by the addition ofwater (100 mL). The resulting solution was extracted with ethyl acetate(3×100 mL). The organic layers were combined and washed with brine (100mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum. The residue was purified by silica gel column eluted withEA/hexane (v/v=4/1). This resulted in 16.459 g of(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneas red oil. LCMS: m z=485 [M+1]⁺.

Step 5.(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Into a 20-mL sealed tube purged with nitrogen and maintained with aninert atmosphere of nitrogen, was placed(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (1.485 g, 3.06 mmol),(5-amino-2,3,4-trifluorophenyl)boronic acid (0.773 g, 4.09 mmol),Pd(PPh₃)₄ (0.356 g, 0.31 mmol), Na₂CO₃ (0.372 g, 3.51 mmol), dioxane (10mL) and water (2 mL). The reaction mixture was stirred at 80° C. for 1h. The reaction mixture was filtered and concentrated under vacuum. Theresidue was purified by silica gel column eluted with EA/hexane(v/v=2/1). This resulted in 1.386 g (76%) of(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneas yellow solid. LCMS: m z=596 [M+1]⁺.

Step 6.4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1)

Into a 100-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(1.444 g, 2.42 mmol), NCS (1.268 g, 9.50 mmol) and AcOH (20 mL). Themixture was stirred at r.t. for 1 d. The reaction was then quenched bythe addition of water (10 mL). The resulting solution was extracted withethyl acetate (3×10 mL). The organic layers were combined and washedwith brine (1×50 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC elutedwith CH₃CN/H₂O (v/v=6/4). This resulted in 69 mg (5%) of4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 1) as yellow solid. LCMS: m z=630 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.38-8.222 (m, 2H), 7.16 (t, J=4.1 Hz, 1H),6.87-6.60 (m, 1H), 6.23 (d, J=16.0 Hz, 1H), 5.75 (dd, J=10.6, 1.8 Hz,1H), 5.13-4.89 (m, 1H), 4.59-4.26 (m, 2H), 4.22-3.94 (m, 1H), 3.92-3.44(m, 3H), 2.75 (s, 1H), 1.93 (d, J=12.4 Hz, 3H), 1.50-1.32 (m, 3H), 1.10(d, J=6.4 Hz, 3H), 1.01-0.82 (m, 3H).

Step 7.4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 1-1) &4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 1-2)

The mixture of4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneatropisomers (140 mg) was purified by Chiral-Prep-HPLC with thefollowing conditions: Column: CHIRALPAK IF, 2 cm×25 cm, 5 um; mobilephase: (Hexane:DCM(v/v=3:1)):IPA(v/v=4:1); detected wavelength: UV 220nm. This resulted in 29 mg (20.7%) of4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 1-1) as a yellow solid. LCMS: mz=630 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.48 (t, J=8.6 Hz, 1H), 8.37 (t, J=10.0 Hz,1H), 7.44 (d, J=5.2 Hz, 1H), 6.84 (td, J=16.5, 10.9 Hz, 1H), 6.30 (t,J=15.7 Hz, 1H), 5.88-5.77 (m, 1H), 5.06 (s, 1H), 4.49 (dd, J=38.5, 12.4Hz, 2H), 4.15 (dd, J=49.6, 13.5 Hz, 1H), 3.95-3.57 (m, 2H), 3.51-3.32(m, 1H), 2.96 (s, 1H), 2.11 (t, J=14.0 Hz, 3H), 1.51 (s, 3H), 1.24 (d,J=6.8 Hz, 3H), 1.06 (dd, J=11.4, 6.9 Hz, 3H). And 28 mg (20.0%) of4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 1-2) as a yellow solid. LCMS: mz=630 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.48 (t, J=8.6 Hz, 1H), 8.37 (t, J=10.0 Hz,1H), 7.44 (d, J=5.2 Hz, 1H), 6.84 (td, J=16.5, 10.9 Hz, 1H), 6.30 (t,J=15.7 Hz, 1H), 5.88-5.77 (m, 1H), 5.06 (s, 1H), 4.49 (dd, J=38.5, 12.4Hz, 2H), 4.15 (dd, J=49.6, 13.5 Hz, 1H), 3.95-3.57 (m, 2H), 3.51-3.32(m, 1H), 2.96 (s, 1H), 2.11 (t, J=14.0 Hz, 3H), 1.51 (s, 3H), 1.24 (d,J=6.8 Hz, 3H), 1.06 (dd, J=11.4, 6.9 Hz, 3H).

Example 24-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2);(M)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2-1); and(P)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2-2)

Step 1.4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2)

Into a 20-mL round-bottom flask purged with nitrogen and maintained withan inert atmosphere of nitrogen was placed(S)-4-(4-acryloyl-2-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(0.71 g, 1.46 mmol), (2-amino-3,4,5,6-tetrafluorophenyl)boronic acid(1.512 g, 7.24 mmol), Pd(PPh₃)₄ (0.183 g, 0.16 mmol), Na₂CO₃ (0.491 g,4.63 mmol), dioxane (8 mL) and water (2 mL). The reaction mixture wasstirred at 80° C. for 1 h. The reaction mixture was filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC elutedwith CH₃CN/H₂O (0.05% NH₄HCO₃) (v:v=2/1). This resulted in 0.181 g (30%)of4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2) as yellow solid. LCMS: m/z=614 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (d, J=4.4 Hz, 1H), 8.28 (s, 1H), 7.21 (s,1H), 6.76 (d, J=12.2 Hz, 1H), 6.23 (d, J=15.6 Hz, 1H), 5.75 (d, J=10.4Hz, 1H), 5.16-4.83 (m, 2H), 4.64-4.20 (m, 2H), 4.20-3.89 (m, 1H),3.89-3.40 (m, 2H), 2.77 (s, 1H), 1.95 (s, 3H), 1.57-1.28 (m, 3H),1.28-1.02 (m, 3H), 0.93 (d, J=5.5 Hz, 3H).

Step 2. (M)-tert-butyl(3S)-4-(7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate

Into a reactor purged with nitrogen and maintained with an inertatmosphere of nitrogen was placed tert-butyl(3S)-4-{7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylate (1.0 eq)(which was on the page 64 and referred as “PIPAZOLINE” in theWO2020102730A1), Pd(dppf)Cl₂.CH₂Cl₂ (0.02 eq), NaOAc (4.0 eq) anddioxane (4.0V). This was followed by the addition of H₂O (3.0 V) at65-85° C. Then (2-amino-3,4,5,6-tetrafluorophenyl)boronic acid (1.15 eq)in dioxane (2.70 V) and H₂O (0.30 V) was added. The reaction mixture wasstirred at 75±5° C. for 1 h. Palladium was removed with sulfhydryl geland crystallized with EA, MTBE and heptane to give (M)-tert-butyl(3S)-4-(7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylateas light yellow solid. LCMS: m/z=660 [M+1]⁺.

Step 3.(M)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2-1)

Into a reactor purged with nitrogen and maintained with an inertatmosphere of nitrogen was placed (M)-tert-butyl(3S)-4-(7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazine-1-carboxylate(1.0 eq) and DCM (10 V). Trimethylsilyl trifluoromethanesulfonate (3.5eq) was added at 5±5° C. The reaction was allowed to react for 1 h at20±5° C. The reaction mixture was washed with K₂CO₃ aqueous solution andbrine to give a solution of(M)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)-2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one.K₃PO₄ solution (5 V, 1.15 eq) was added to the solution of(M)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)-2-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one.This was followed by the addition of acryloyl chloride (1.15 eq) at0-10° C. The reaction was separated, washed with 5% brine andconcentrated under vacuum. The crude product was crystallized with EtOHto give(M)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2-1) LCMS: m/z=614 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.37 (d, J=4.8 Hz, 1H), 8.39-8.25 (m, 1H),7.20 (d, J=4.6 Hz, 1H), 6.93-6.72 (m, 1H), 6.22 (d, J=15.9 Hz, 1H), 5.74(d, J=10.5 Hz, 1H), 4.92 (s, 1H), 4.57-4.27 (m, 2H), 4.26-4.02 (m, 1H),3.79-3.49 (m, 2H), 3.35-3.23 (m, 1H), 2.85-2.70 (m, 1H), 1.94 (s, 3H),1.55-1.34 (m, 3H), 1.10 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.5 Hz, 3H).

Step 4.(P)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2-2)

(P)-4-((S)-4-acryloyl-2-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 2-2) was afforded with the basically same procedure as thepreparation of Compound 2-1 except that the tert-butyl(3S)-4-{7-chloro-6-fluoro-(1M)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylatewas replaced with tert-butyl(3S)-4-{7-chloro-6-fluoro-(1P)-1-[4-methyl-2-(propan-2-yl)pyridin-3-yl]-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl}-3-methylpiperazine-1-carboxylatein the step 2. LCMS: m z=614 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.46 (d, J=5.0 Hz, 1H), 8.42-8.33 (m, 1H),7.33-7.25 (m, 1H), 6.91-6.76 (m, 1H), 6.32 (dd, J=16.7, 4.7 Hz, 1H),5.84 (dd, J=10.6, 1.9 Hz, 1H), 5.28-5.08 (m, 1H), 4.63-4.36 (m, 2H),4.24-4.03 (m, 1H), 3.96-3.79 (m, 1H), 3.79-3.54 (m, 1H), 3.45-3.35 (m,0.5H), 3.26-3.15 (m, 0.5H), 2.89-2.76 (m, 1H), 2.12-1.99 (m, 3H), 1.46(d, J=6.6 Hz, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.7 Hz, 3H).

Example 34-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (Compound 3);(M)-4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;and(P)-4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Step 1. tert-butyl4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

Into a 500-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(8.24 g, 23.63 mmol), POCl₃ (7.37 g, 48.06 mmol), DIEA (8.32 g, 64.37mmol) and acetonitrile (80 mL). The mixture was stirred at 70° C. for 1h. The reaction was cooled to room temperature and concentrated undervacuum. This resulted in4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-onewhich was used directly in next step.

Into a 250-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(crude) and acetonitrile (80 mL). DIEA (6.01 g, 46.50 mmol) andtert-butyl piperazine-1-carboxylate (544 g, 29.21 mmol) were added. Thereaction mixture was stirred for 1 h at room temperature. The reactionwas then quenched by the addition of water (50 mL). The reaction wasconcentrated under vacuum. The residue was purified by silica gel columneluted with EA/hexane(v/v=3/2). This resulted in 4.38 g (36% in twosteps) of tert-butyl4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylateas yellow solid. LCMS: m z=517 [M+1]⁺.

Step 2.4-(4-acryloylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Into a 250-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed tert-butyl4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate(4.37 g, 8.45 mmol), TFA (15 ml) and DCM (40 mL). The reaction mixturewas stirred at room temperature for 0.5 h. The reaction mixture wasconcentrated under vacuum. The residue was dissolved by DCM (40 mL) in100-mL round-bottom flask. TEA (5.30 g, 52.37 mmol) was added. Thereaction mixture was cooled to 0° C. and acryloyl chloride (0.90 g, 9.94mmol) was added. The mixture stirred at room temperature for 1 h. Thereaction was concentrated under vacuum. The residue was purified bysilica gel column eluted with EA/hexane (v/v=1/1). This resulted in 1.50g (23%) of4-(4-acryloylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneas yellow solid. LCMS: m z=471 [M+1]⁺.

Step 3.4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 3)

Into a 40-mL sealed tube purged with nitrogen and maintained with aninert atmosphere of nitrogen, was placed4-(4-acryloylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(1.42 g, 3.02 mmol),2,3,4,5-tetrafluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline(3.32 g, 9.68 mmol), Pd(PPh₃)₄ (0.77 g, 0.67 mmol), Na₂CO₃ (1.04 g, 9.81mmol), dioxane (15 mL) and water (1.5 mL). The reaction mixture wasstirred at 80° C. for 1 h. The reaction mixture was filtered andconcentrated under vacuum. The reaction mixture was concentrated undervacuum. The residue was purified by Prep-HPLC eluted with CH₃CN/H₂O(v/v=7/3)). This resulted in 535 mg (30% yield) of4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 3) as yellow solid. LCMS: m/z=600 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50-8.43 (m, 2H), 7.29 (dd, J=5.0, 0.8 Hz,1H), 6.82 (dd, J=16.8, 10.6 Hz, 1H), 6.30 (dd, J=16.8, 2.0 Hz, 1H), 5.83(dd, J=10.6, 2.0 Hz, 1H), 4.26-4.09 (m, 4H), 4.03-3.85 (m, 4H),2.91-2.78 (m, 1H), 2.04 (d, J=3.6 Hz, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.02(d, J=6.8 Hz, 3H).

Step 4.4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 3-1) &4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (the second elutingisomer, Compound 3-2)

The mixture of4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneatropisomers (550 mg) was purified by Chiral-Prep-HPLC with thefollowing conditions: Column: CHIRALPAK IF, 2 cm×25 cm, 5 um; mobilephase: (Hex:DCM(v/v=3:1)):EtOH(v/v=9:1); detected wavelength: UV 220 nm.This resulted in 255 mg (46.36%) of4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 3-1) as a yellow solid. LCMS:m/z=600 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50-8.43 (m, 2H), 7.32-7.26 (m, 1H), 6.82(dd, J=16.8, 10.6 Hz, 1H), 6.30 (dd, J=16.8, 2.0 Hz, 1H), 5.83 (dd,J=10.6, 2.0 Hz, 1H), 4.26-4.09 (m, 4H), 4.03-3.86 (m, 4H), 2.93-2.78 (m,1H), 2.04 (s, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H).

And 247 mg (44.91%) of4-(4-acryloylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 3-2) as a yellow solid. LCMS:m/z=600 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50-8.43 (m, 2H), 7.29 (dd, J=5.0, 0.8 Hz,1H), 6.82 (dd, J=16.8, 10.6 Hz, 1H), 6.30 (dd, J=16.7, 1.9 Hz, 1H), 5.83(dd, J=10.6, 2.0 Hz, 1H), 4.26-4.09 (m, 4H), 4.04-3.85 (m, 4H),2.94-2.78 (m, 1H), 2.04 (s, 3H), 1.19 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.8Hz, 3H).

Example 44-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(“Compound 4”);(M)-4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;(P)-4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Step 1. 2,2,2-trifluoro-N-(2,3,4,5-tetrafluorophenyl)acetamide

Into a 1000-mL three-neck bottom flask purged with nitrogen andmaintained with an inert atmosphere of nitrogen, was placed2,3,4,5-tetrafluoroaniline (29.64 g, 179.54 mmol), TEA (49.02 g, 484.43mmol), DCM (300 mL) and stirred. The mixture was cooled to 0° C. andthen trifluoroacetic anhydride (61.67 g, 293.62 mmol) was added. Theresulting solution was stirred for further 2 h at room temperature. Thesolution was concentrated under vacuum. The crude was then quenched bythe addition of water (500 mL). The resulting solution was extractedwith EA (3×200 mL). The organic layers were combined, then washed withsodium bicarbonate solution (200 mL) and brine (300 mL), dried overanhydrous Na₂SO₄. the residue was concentrated under vacuum. Thisresulted in 53.45 g (crude) of 2,2,2-trifluoro-N-(2,3,4,5-tetrafluorophenyl)acetamide. LCMS: m z=260 [M-H]⁻.

Step 2. (2-amino-3,4,5,6-tetrafluorophenyl)boronic acid

Into a 1000-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed2,2,2-trifluoro-N-(2,3,4,5-tetrafluorophenyl)acetamide (25.03 g, 95.90mmol) and THF (250 mL). The mixture was cooled to −65° C. and thenn-butyl lithium solution (88 mL, 223.46 mmol) was added. The mixture wasstirred at −50° C. for 1 h. Then trimethyl borate (30.24 g, 290.95 mmol)was added dropwise at −70° C. The mixture was stirred at roomtemperature for 1 h. The reaction was then quenched by the addition of4N HCl solution (200 mL). The mixture was stirred at room temperaturefor 0.5 h. The resulting solution was extracted with EA (2×200 mL). Theorganic layers were combined, then washed with sodium bicarbonatesolution (200 mL) and brine (200 mL), dried over anhydrous Na₂SO₄. Theresidue was concentrated under vacuum. The crude was stirred with themixture of Hex/EA (v/v=20/1)(70 mL) for 1 h. The resulting solid wasfiltered to provide 5.10 g (25.50% yield) of(2-amino-3,4,5,6-tetrafluorophenyl)boronic acid as off-white solid.LCMS: m z=210 [M+1]⁺.

Step 3.2,3,4,5-tetrafluoro-6-((3aR,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)aniline

Into a 250-mL round-bottom flask was placed(2-amino-3,4,5,6-tetrafluorophenyl) boronic acid (11.82 g, 56.58 mmol),(1S,3R,4S,5S)-4,6,6-trimethylbicyclo[3.1.1]heptane-3,4-diol (9.56 g,56.58 mmol) and toluene (120 mL). The mixture was stirred for 3 h at 55°C. The residue was concentrated under vacuum and purified by a silicagel column eluted with Hex/EA (v/v=20/1). This resulted 17.08 g (87.98%yield) of2,3,4,5-tetrafluoro-6-((3aR,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)anilineas brown solid. LCMS: m z=344 [M+1]⁺.

Step 4. tert-butyl(R)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate

Into a 50-mL round-bottom flask purged with nitrogen and maintained withan inert atmosphere of nitrogen, was placed7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione(7.24 g, 0.02 mol), POCl₃ (7.95 g, 0.05 mol), DIEA (12.12 g, 0.12 mol)and acetonitrile (30 mL). The mixture was stirred at 80° C. for 2 h. Thereaction was cooled to room temperature and concentrated under vacuum.This resulted in4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one which was used directly in next step.

Into a 100-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(crude) and acetonitrile (80 mL), followed by the addition of DIEA(12.12 g, 0.12 mol) and tert-butyl (R)-2-methylpiperazine-1-carboxylate(4.01 g, 0.02 mol). The reaction mixture was stirred for 0.5 h at roomtemperature. The reaction was then quenched by the addition of water(300 mL). The resulting solution was extracted with ethyl acetate (2×300mL). The organic layers were combined and washed with brine (50 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by silica gel column eluted with EA/hexane(v:v=9/1). This resulted in 3.208 g (30% in two steps) of tert-butyl(R)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylateas yellow solid. LCMS: m z=531 [M+1]⁺.

Step 5.(R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Into a 50-mL round-bottom flask purged with nitrogen and maintained withan inert atmosphere of nitrogen, was placed tert-butyl(R)-4-(7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylate(3.208 g, 6.04 mol), TFA (25 ml) and DCM (75 mL). The reaction mixturewas stirred for 1 h at room temperature and concentrated under vacuum.This resulted in(R)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one as crude, which was useddirectly in the next step.

Into a 50-mL round-bottom flask and maintained with an inert atmosphereof nitrogen, was placed(R)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)-4-(3-methylpiperazin-1-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(crude), ACN (75 mL), DIEA (1.45 g, 12.08 mmol) and acryloyl chloride(0.549 g, 6.06 mmol). The reaction mixture was stirred at roomtemperature for 0.5 h. The reaction was then quenched by the addition ofwater (100 mL), extracted with ethyl acetate (3×200 mL). The organiclayers were combined and washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel column eluted with EA/hexane (v:v=4/1). Thisresulted in 2.38 g (82% in two steps) of(R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneas yellow solid. LCMS: m z=485[M+1]⁺.

Step 6.4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 4)

Into a 20-mL sealed tube purged with nitrogen and maintained with aninert atmosphere of nitrogen, was placed(R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (1.224 g, 2.52 mmol),2,3,4,5-tetrafluoro-6-((3aR,4R,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)aniline(1.794 g, 5.223 mmol), Pd(PPh₃)₄ (0.614 g, 0.53 mmol), Na₂CO₃ (0.72 g,6.79 mmol), dioxane (12 mL) and water (1 mL). The reaction mixture wasstirred at 80° C. for 2 h. The reaction mixture was filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC elutedwith ACN/H₂O (1% NH₄HCO₃) (v:v=7/3). This resulted in 740 mg (47.8% intwo steps) of4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 4) as yellow solid. LCMS: m z=614 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.52-8.43 (m, 2H), 7.29 (d, J=5.0 Hz, 1H),6.81 (dd, J=16.8, 10.6 Hz, 1H), 6.29 (d, J=16.5 Hz, 1H), 5.81 (d, J=10.4Hz, 1H), 4.58-4.26 (m, 3H), 4.11-3.72 (m, 4H), 2.81-2.83 (m, 1H), 2.05(d, J=18.6 Hz, 3H), 1.39 (s, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.01-1.02 (m,3H).

Step 7.4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 4-1) &4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 4-2)

The mixture of4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneatropisomers (710 mg) was purified by Chiral-Prep-HPLC with thefollowing conditions: Column: CHIRAL ART Amylose-SA, 3 cm×25 cm, 5 um;mobile phase: CO₂: IPA(v/v=62:38); detected wavelength: UV 220 nm. Thisresulted in 223 mg (40.58%) of4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 4-1) as a yellow solid. LCMS: mz=614 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.46 (dd, J=7.3, 5.0 Hz, 2H), 7.34-7.21 (m,1H), 6.81 (dd, J=16.7, 10.6 Hz, 1H), 6.29 (d, J=16.7 Hz, 1H), 5.81 (d,J=11.0 Hz, 1H), 4.58-4.32 (m, 3H), 3.98-3.77 (m, 4H), 2.75-2.77 (m, 1H),2.07 (s, 3H), 1.50-1.30 (m, 3H), 1.18 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8Hz, 3H).

And 236 mg (38.84%) of4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 4-2) as a yellow solid. LCMS: mz=614 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J=8.9 Hz, 1H), 8.40 (d, J=5.0 Hz,1H), 7.24 (d, J=4.5 Hz, 1H), 6.81 (dd, J=16.9, 10.4 Hz, 1H), 6.29 (d,J=16.9 Hz, 1H), 5.81 (d, J=10.5 Hz, 1H), 4.40-4.42 (m, 3H), 4.08-3.80(m, 4H), 2.87-2.69 (m, 1H), 2.02 (s, 3H), 1.48-1.32 (m, 3H), 1.20-1.16(m, 3H), 1.00 (d, J=6.8 Hz, 3H).

Example 54-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 5);(M)-4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;and(P)-4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Step 1.4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Into a 250-mL round-bottom flask purged with nitrogen and maintainedwith an inert atmosphere of nitrogen, was placed7-chloro-6-fluoro-4-hydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(7.75 g, 22.22 mmol), POCl₃ (8.75 g, 57.08 mmol), DIEA (10.00 g, 77.35mmol) and acetonitrile (80 mL). The mixture was stirred at 80° C. for 1h. The reaction was cooled to room temperature and concentrated undervacuum. Into a 250-mL round-bottom flask purged with nitrogen andmaintained with an inert atmosphere of nitrogen, was placed4,7-dichloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(8.17 g, 22.22 mmol) and acetonitrile (80 mL). DIEA (3.24 g, 25.09 mmol)and (2R,6S)-2,6-dimethylpiperazine (2.36 g, 20.69 mmol) were added. Thereaction mixture was stirred for 0.5 h at room temperature. The reactionmixture was cooled to 0° C. and acryloyl chloride (1.65 g, 18.21 mmol)was added. The reaction was then quenched by the addition of water (50mL). The resulting solution was extracted with ethyl acetate (3×150 mL).The organic layers were combined and washed with brine (50 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidues was purified by silica gel column eluted with MeOH/EA(v/v=1/10). This resulted in 3.70 g (33% in two steps) of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneas yellow oil. LCMS: m z=499 [M+1]⁺.

Step 2.4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 5)

Into a 20-mL round-bottom flask was placed4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(0.295 g, 0.59 mmol), (2-amino-3,4,5,6-tetrafluorophenyl)boronic acid(0.348 g, 1.67 mmol), Pd(PPh₃)₄ (0.140 g, 0.12 mmol), Na₂CO₃ (0.214 g,2.02 mmol), dioxane (5 mL) and water (1 mL). The reaction mixture wasstirred at 80° C. for 1 h. The reaction mixture was filtered andconcentrated under vacuum. The residue was purified by Prep-HPLC elutedwith CH₃CN/H₂O (0.05% NH₄HCO₃) (v:v=2/1). This resulted in 0.111 g (30%)of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 5) as yellow solid. LCMS: m z=628 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.39-8.32 (m, 2H), 7.21 (d, J=5.0 Hz, 1H),6.77-6.70 (m, 1H), 6.24-6.18 (m, 1H), 5.78-5.69 (m, 1H), 4.60 (s, 2H),4.46-4.35 (m, 2H), 3.77-3.67 (m, 2H), 2.74-2.66 (m, 1H), 1.97 (s, 3H),1.43 (d, J=6.9 Hz, 3H), 1.37 (d, J=7.0 Hz, 3H), 1.09 (d, J=6.8 Hz, 3H),0.93 (d, J=6.8 Hz, 3H).

Step 3.4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 5-1) &4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 5-2)

The mixture of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneatropisomers (408 mg) was purified by Chiral-Prep-HPLC with thefollowing conditions: Column: CHIRALPAK IG, 3 cm×25 cm, 5 um; mobilephase: (Hex:DCM=3:1(v/v)):EtOH(v/v=92:8); detected wavelength: UV 220nm. This resulted in 148 mg (36.27%) of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 5-1) as a yellow solid. LCMS: mz=628 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.39-8.31 (m, 2H), 7.20 (d, J=5.0 Hz, 1H),6.79-6.68 (m, 1H), 6.24-6.16 (m, 1H), 5.75-5.68 (m, 1H), 4.56 (d, J=40.4Hz, 2H), 4.48-4.26 (m, 2H), 3.89-3.61 (m, 2H), 2.76-2.64 (m, 1H), 1.96(s, 3H), 1.54-1.28 (m, 6H), 1.09 (d, J=6.8 Hz, 3H), 0.97-0.81 (m, 3H).

And 159 mg (38.97%) of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(2-amino-3,4,5,6-tetrafluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 5-2) as a yellow solid. LCMS: mz=628 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.40-8.30 (m, 2H), 7.20 (d, J=5.0 Hz, 1H),6.78-6.67 (m, 1H), 6.25-6.16 (m, 1H), 5.78-5.67 (m, 1H), 4.56 (d, J=38.1Hz, 2H), 4.51-4.33 (m, 2H), 3.83-3.66 (m, 2H), 2.78-2.70 (m, 1H), 1.96(s, 3H), 1.48-1.38 (m, 3H), 1.36 (d, J=6.9 Hz, 3H), 1.09 (d, J=6.8 Hz,3H), 0.92 (d, J=6.8 Hz, 3H).

Example 64-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 6)

Step 1.(R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Into a 20-mL sealed tube purged with nitrogen and maintained with aninert atmosphere of nitrogen, was placed(R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(1.02 g, 2.47 mmol), (5-amino-2,3,4-trifluorophenyl)boronic acid (0.94g, 4.92 mmol), Pd(PPh₃)₄ (0.59 g, 0.51 mmol), Na₂CO₃ (0.738 g, 6.96mmol), dioxane (30 mL) and water (2 mL). The reaction mixture wasstirred at 80° C. for 4 h. The reaction mixture was filtered andconcentrated under vacuum. The residue was purified by silica gel columneluted with ACN/H₂O (v/v=7/3). This resulted in 200 mg (crude) of(R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneas yellow solid. LCMS: m z=596 [M+1]⁺.

Step 2.4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 6)

Into a 50-mL round-bottom flask purged with nitrogen and maintained withan inert atmosphere of nitrogen, was placed(R)-4-(4-acryloyl-3-methylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(200 mg, 0.34 mmol), NCS (111 mg, 0.83 mmol) and AcOH (3 mL). Thereaction mixture was stirred for 48 h at room temperature. The reactionwas then quenched by the addition of water (100 mL). The resultingsolution was extracted with ethyl acetate (2×100 mL). The organic layerswere combined and washed with brine (10 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under vacuum. The residues waspurified by Prep-HPLC eluted with ACN/H₂O (0.5% NH₄HCO₃) (v/v=7/3)).This resulted in 17 mg of4-((R)-4-acryloyl-3-methylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 6) as yellow solid. LCMS: m z=630[M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.50 (d, J=8.9 Hz, 1H), 8.40 (d, J=5.0 Hz,1H), 7.24 (d, J=4.5 Hz, 1H), 6.81 (dd, J=16.9, 10.4 Hz, 1H), 6.29 (d,J=16.9 Hz, 1H), 5.81 (d, J=10.5 Hz, 1H), 4.40-4.41 (m, 3H), 4.15-3.55(m, 4H), 2.87-2.69 (m, 1H), 2.07-1.94 (m, 3H), 1.49-1.33 (m, 3H),1.20-1.16 (m, 3H), 1.01-1.03 (m, 3H).

Example 74-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(Compound 7);(M)-4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one;and(P)-4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Step 1.4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Into a 20-mL round-bottom flask was placed4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(2.50 g, 5.01 mmol), (5-amino-2,3,4-trifluorophenyl)boronic acid (3.08g, 16.15 mmol), Pd(PPh₃)₄ (0.45 g, 0.39 mmol), Na₂CO₃ (0.98 g, 9.21mmol), dioxane (20 mL) and water (4 mL). The reaction mixture wasstirred at 80° C. for 1 h. The reaction mixture was filtered andconcentrated under vacuum. The residue was purified by C₁₈ column elutedwith CH₃CN/H₂O (v/v=2/1). This resulted in 0.476 g of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneas yellow solid. LCMS: m z=610 [M+1]⁺.

Step 2.4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one

Into a 20-mL round-bottom flask was placed4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(5-amino-2,3,4-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one (0.476 g, 0.78 mmol), NCS (0.212 g, 1.59 mmol) and HOAc (5 mL).The reaction mixture was stirred at room temperature for 1 day. Thereaction mixture was filtered and concentrated under vacuum.

The residue was purified by C₁₈ eluted with CH₃CN/H₂O (0.05% NH₄HCO₃)(v/v=1/1). This resulted in 181 mg (37%) of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneas off-white solid. LCMS: m z=644 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=8.9 Hz, 1H), 8.40 (d, J=5.0 Hz,1H), 7.27-7.22 (m, 1H), 6.92-6.77 (m, 1H), 6.37-6.22 (m, 1H), 5.84-5.75(m, 1H), 4.70 (s, 2H), 4.60-4.40 (m, 2H), 3.91-3.71 (m, 2H), 2.87-2.74(m, 1H), 2.11-1.99 (m, 3H), 1.60-1.37 (m, 6H), 1.18 (d, J=6.8 Hz, 3H),1.04-0.93 (m, 3H).

Step 3.4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting, Compound 7-1) &4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 7-2)

The mixture of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-oneatropisomers (180 mg) was purified by Chiral-Prep-HPLC with thefollowing conditions: Column: CHIRALPAK IF, 2 cm×25 cm, 5 um; mobilephase: (Hex:DCM(v/v=3:1)):IPA(v/v=90:10); detected wavelength: UV 220nm. This resulted in 81 mg (45%) of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the first eluting isomer, Compound 7-1) as off-white solid. LCMS: mz=644 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=8.9 Hz, 1H), 8.40 (d, J=5.0 Hz,1H), 7.31-7.20 (m, 1H), 6.86-6.77 (m, 1H), 6.34-6.25 (m, 1H), 5.87-5.76(m, 1H), 4.81-4.62 (m, 2H), 4.62-4.39 (m, 2H), 3.92-3.75 (m, 2H),2.85-2.72 (m, 1H), 2.03 (d, J=10.7 Hz, 3H), 1.56-1.39 (m, 6H), 1.18 (d,J=6.8 Hz, 3H), 1.04-0.95 (m, 3H).

And 79 mg (43.89%) of4-((3S,5R)-4-acryloyl-3,5-dimethylpiperazin-1-yl)-7-(3-amino-2-chloro-4,5,6-trifluorophenyl)-6-fluoro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one(the second eluting isomer, Compound 7-2) as off-white solid. LCMS: mz=644 [M+1]⁺.

¹H NMR (400 MHz, CD₃OD) δ 8.47 (d, J=8.9 Hz, 1H), 8.40 (d, J=5.0 Hz,1H), 7.32-7.18 (m, 1H), 6.86-6.75 (m, 1H), 6.32-6.22 (m, 1H), 5.86-5.75(m, 1H), 4.70 (s, 2H), 4.60-4.38 (m, 2H), 3.87-3.76 (m, 2H), 2.86-2.71(m, 1H), 2.03 (d, J=10.7 Hz, 3H), 1.60-1.42 (m, 6H), 1.18 (d, J=6.8 Hz,3H), 1.07-0.92 (m, 3H).

The following compound can be synthesized:

Pharmacological Testing

1. SOS1 Catalyzed Nucleotide Exchange Assay

HIS-KRAS(G12C, a4 2-185, Sino biological) was diluted to 5 M in EDTAbuffer (20 mM HEPES, pH 7.4, 50 mM NaCl, 10 mM EDTA, 0.01% (v/v)Tween-20) and incubated for 30 min at 25° C. The EDTA pretreatedHIS-KRAS(G12C) was diluted to 12 nM in assay buffer (25 mM HEPES, pH7.4, 120 mM NaCl, 5 mM MgCl₂, 1 mM DTT, 0.01% (v/v) Tween 20, 0.1% (w/v)BSA) containing 120 nM GDP(Sigma) and MAb Anti 6HIS-Tb cryptateGold(Cisbio) and incubated for 1 hour at 25° C. to prepare GDP-loadedHIS-KRAS(G12C). The GDP-loaded HIS-KRAS(G12C) was pre-incubation withdiluted compounds in a 384-well plate (Greiner) for 1 hour, thenpurified SOS1 ExD(Flag tag, aa 564-1049) and BODIPY™ FL GTP (Invitrogen)were added to the assay wells (Final concentration: 3 nM HIS-KRAS(G12C),2 μM SOS1 ExD, 80 nM BODIPY™ FL GTP, 21 ng/mL MAb Anti 6HIS-Tb cryptateGold) and incubated for 4 hours at 25° C. TR-FRET signals were then readon Tecan Spark multimode microplate reader. The parameters were F486:Excitation 340 nm, Emission 486 nm, Lag time 100 is, Integration time200 is; F515: Excitation 340 nm, Emission 515 nm, Lag time 100 is,Integration time 200 is. TR-FRET ratios for each individual wells werecalculated by equation: TR-FRET ratio=(Signal F515/Signal F486)*10000.Then the data were analyzed using a 4-parameter logistic model tocalculate IC₅₀ values. The results of the SOS1 catalyzed nucleotideexchange assay are in the following Table 2:

TABLE 2 SOS1 catalyzed nucleotide Compound exchange IC₅₀(nM) Compound 17.25 Compound 1-1 4.08 Compound 1-2 121 Compound 2 2.04 Compound 2-11.19 Compound 2-2 61.8 Compound 3 5.51 Compound 3-1 3.14 Compound 3-2234 Compound 4 10.3 Compound 4-1 3.31 Compound 4-2 278 Compound 5 5.41Compound 5-1 3.30 Compound 5-2 96.1 Compound 6 40.1 Compound 7 17.5Compound 7-1 6.54 Compound 7-2 307 Amg-510 2.12

Amg-510 has the following structure:

From the Table 2, it can be seen that the representative compounds inthe present invention have good inhibitory activity under the SOS1catalyzed nucleotide exchange assay, especially the Compound 2-1. Theinhibitory activity of the Compound 2-1 can reach about 2 times as muchas that of the control compound Amg-510.

2. Phospho-ERK1/2(THR202/TYR204) HTRF Assay

NCI-H358 cells expressing KRAS G12C mutant protein were cultured in RPMI1640 medium (Gibco) containing 10% fetal bovine serum (Gibco). TheNCI-H358 cells in culture medium were seeded in 96-well plates at aconcentration of 40,000 cells/well and then put in a 37° C./5% CO₂ cellincubator to incubate overnight. In the next day, the culture medium wasremoved and the compound diluted in assay medium (RPMI 1640, 0.1% FBS)was added in each well. After 2 hours incubation in a 37° C./5% CO₂ cellincubator, the assay medium in 96-well plates was removed, then 50 μL of1× blocking reagent-supplemented lysis buffer (Cisbio) was added and theplates were incubated at 25° C. for 45 min with shaking. 10 μL of celllysates from the 96-well plates were transferred to a 384-well plate(Greiner) containing 2.5 μL/well HTRF® pre-mixed antibodies (Cisbio64AERPEH). Incubate 4 hours at 25° C. and then read HTRF signals onTecan Spark multimode microplate reader. The data were analyzed using a4-parameter logistic model to calculate IC₅₀ values. The results of thePhospho-ERK1/2(THR202/TYR204) HTRF assay are in the following Table 3:

TABLE 3 p-ERK Compound IC₅₀(nM) Compound 1 70.1 Compound 1-1 16.6Compound 1-2 ND Compound 2 30.7 Compound 2-1 14.5 Compound 2-2 681  Compound 3 ND Compound 3-1 25.4 Compound 3-2 ND Compound 4 ND Compound4-1 40.9 Compound 4-2 ND Compound 5 48.8 Compound 5-1 17.8 Compound 5-2774   Compound 6 ND Compound 7 ND Compound 7-1 36.7 Compound 7-2 NDAmg-510 24.5 ND refers to Not Detected.

ND refers to Not Detected.

From the Table 3, it can be seen that the representative compounds inthe present invention have good inhibition activity underphospho-ERK1/2(THR202/TYR204) HTRF assay, especially the Compound 2-1.The inhibitory activity of the Compound 2-1 can reach about 2 times asmuch as that of the control compound Amg-510.

3. Mouse Pharmacokinetic Study

The purpose of this study was to evaluate the pharmacokinetic propertiesof compounds in Balb/c mouse (♀) following single dose administration.The day before administration, mice were fasted overnight and freeaccess to water. Six mice were needed for each compound and the six micewere divided into two groups (n=3/group), group A and group B. Mice ingroup A were treated with a single 3 mg/kg dose of compound (iv). Micein group B were treated with a single 10 mg/kg dose of compound (po).For each mouse in group A, blood samples were collected at pre-dose, andat the time point of 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post-dose.For each mouse in group B, blood samples were collected at pre-dose, andat the time point of 0.25, 0.5, 1, 2, 3, 4, 6, 8 and 24 h post-dose.Blood samples were placed on ice until centrifugation to obtain plasmasamples. The plasma samples were stored at −80° C. until analysis. Theconcentration of compound in plasma samples was determined using aLC-MS/MS method. The results are in the following Table 4:

TABLE 4 3 mg/kg, iv 10 mg/kg, po CL Vss C_(max) AUC_(0-24 h) Oral (mL/(L/ (ng/ (ng · BA Compound min/kg) kg) mL) h/mL) (F %) Compound 2 65.22.31 1437 1147 44.7 Compound 2-1 38.9 1.28 2440 2618 58.9 Amg-510 40.51.64 1603 1812 43.9

From Table 4, it can be seen that the representative Compound 2 andCompound 2-1 have good pharmacokinetic properties in mouse model,especially the Compound 2-1 which has the higher C_(max) andAUC_(0-24 h) comparative with the Amg-510, which makes Compound 2-1 moresuitable for treating cancers with KRAS G12C mutation as an orallytherapeutic active ingredient in clinic.

4. Dog Pharmacokinetic Study

The purpose of this study was to evaluate the pharmacokinetic propertiesof compounds in beagle dog following single dose administration. The daybefore administration, dogs were fasted overnight and free access towater. Four beagle dogs were needed for each compound and the four dogswere divided into two groups, group A and group B (one male(♂) and onefemale (♀) in each group). Dogs in group A were treated with a single 1mg/kg dose of compound (iv). Dogs in group B were treated with a single3 mg/kg dose of compound (po). For dogs in group A, blood samples werecollected at pre-dose, and at the time point of 0.083, 0.25, 0.5, 1, 2,4, 6, 8 and 24 h post-dose. For dogs in group B, blood samples werecollected at pre-dose, and at the time point of 0.25, 0.5, 1, 2, 4, 6, 8and 24 h post-dose. Blood samples were placed on ice untilcentrifugation to obtain plasma samples. The plasma samples were storedat −80° C. until analysis. The concentration of compound in plasmasamples was determined using a LC-MS/MS method. The results are infollowing Table 5:

TABLE 5 1 mg/kg, iv 3 mg/kg, po CL (mL/ V_(SS) C_(max) AUC_(0-24h) OralBA Compound Sex min/kg) (L/kg) (ng/mL) (ng · h/mL) (F %) Compound 2-1 ♂4.15 0.255 4080 7308 60.9 ♀ 4.40 0.295 2330 5022 44.3 Amg-510 ♂ 21.10.535 1840 1994 84.4 ♀ 20.1 0.543 450 404 16.4

From Table 5, it can be seen that Compound 2-1 has excellentpharmacokinetic properties in beagle dog model comparative with theAmg-510. The C_(max) and AUC_(0-24 h) of Compound 2-1 are bothsignificantly more than Amg-510, for example, the AUC_(0-24 h) of theCompound 2-1 in male beagle dog can reach more than 3 times as much asthat of the control compound Amg-510, and the AUC_(0-24 h) of Compound2-1 in female beagle dog can reach more than 12 times as much as that ofthe control compound Amg-510, which makes the Compound 2-1 more suitablefor treating cancers with KRAS G12C mutation as an orally therapeuticactive ingredient in clinic.

5. Cynomolgus Monkey Pharmacokinetic Study

The purpose of this study was to evaluate the pharmacokinetic propertiesof compounds in cynomolgus monkey following single dose administration.The day before administration, monkeys were fasted overnight and freeaccess to water. Four monkeys are needed for each compound and the fourmonkeys were divided into two groups, group A and group B (one male (♂)and one female (♀) in each group). Monkeys in group A were treated witha single 1 mg/kg dose of compound (iv). Monkeys in group B were treatedwith a single 3 mg/kg dose of compound (po). For monkeys in group A,blood samples were collected at pre-dose, and at the time point of0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post-dose. For monkeys in groupB, blood samples were collected at pre-dose, and at the time point of0.25, 0.5, 1, 2, 4, 6, 8 and 24 h post-dose. Blood samples were placedon ice until centrifugation to obtain plasma samples. The plasma sampleswere stored at −80° C. until analysis. The concentration of compound inplasma samples was determined using a LC-MS/MS method. The results arein following Table 6:

TABLE 6 1 mg/kg, iv 3 mg/kg, po CL (mL/ V_(SS) C_(max) AUC_(0-24h) OralBA Compound Sex min/kg) (L/kg) (ng/mL) (ng · h/mL) (F %) Compound ♂ 8.260.555 1580 3253 54.1 2-1 ♀ 8.20 0.507 1060 2494 41.2 Amg-510 ♂ 25.50.775 133 214 11.0 ♀ 84.3 2.01 100 241 41.3

From Table 6, it can be seen that Compound 2-1 has excellentpharmacokinetic properties in monkey model. The C_(max) and AUC_(0-24 h)of Compound 2-1 are significantly more than Amg-510, for example, theAUC_(0-24 h) of the Compound 2-1 in male cynomolgus monkey can reachmore than 15 times as much as that of the control compound Amg-510, andthe AUC_(0-24 h) of Compound 2-1 in female cynomolgus monkey can reachmore than 10 times as much as that of the control compound Amg-510,which makes the Compound 2-1 more suitable for treating cancers withKRAS G12C mutation as an orally therapeutic active ingredient in clinic.

6. The Efficacy in NCI-H1373 (KRAS^(G12C)) Xenograft Model

NCI-H1373 (KRAS^(G12C)) cells (5.0E+06 cells) were injectedsubcutaneously into the right flank of female BALB/c nude mice (6-8weeks) in a mixture with PBS and Matrigel (Corning)(PBS/Matrigel=1:1(v/v)). Mice were monitored daily and calipermeasurements began when tumors became visible. Tumor volume wascalculated by measuring two perpendicular diameters using the formula:(L*W²)/2 in which L and W refer to the length and width tumor diameterrespectively. When the average tumor volume reached 150-200 mm³, micewere grouped randomly (n=6/group) and treated with compounds. Tumorvolume and mice weight was measured twice a week during treatment (˜ 3weeks). Tumor growth inhibition rates were calculated by TGI%=(1−(Vt−Vt₀)/(Vc−Vc₀))*100%, wherein Vc and Vt are the mean tumorvolume of control and treated groups at the end of the studyrespectively, and Vc₀ and Vt₀ are the mean tumor volume of control andtreated groups at the start respectively. The results are in thefollowing Table 7 and FIG. 1:

TABLE 7 Tumor volume Tumor volume at the start, at the end Groups mm³(Day 21), mm³ TGI % Vehicle 193 1879 — Compound 2-1, 192 27 110 10mg/kg, QD

From Table 7 and FIG. 1, it can be seen that the Compound 2-1 hasexcellent efficacy in vivo and the regression of the tumor has beenobserved.

7. Safety Exploration in SW837 (KRAS^(G12C)) xenograft model

SW837 (KRAS^(G12C)) cells (1.0E+07 cells) were injected subcutaneouslyinto the right flank of female NOD SCID mice (6-8 weeks) in a mixturewith PBS and Matrigel (Corning) (PBS/Matrigel=1:1(v/v)). Mice weremonitored daily and caliper measurements began when tumors becamevisible. Tumor volume was calculated by measuring two perpendiculardiameters using the following formula: (L*W²)/2 in which L and W referto the length and width tumor diameter respectively. After mice weregrouped to study the efficacy, the remaining mice (n=8) were used toexplore the safety. The mice were treated with 400 mg/kg Compound 2-1(po, QD) for 22 days, and mice body weight was measured twice a weekduring treatment. The weight of mice varies with the number of daysafter cell inoculation is shown in FIG. 2. From FIG. 2, it can be seenthat the Compound 2-1 has good safety.

It is to be understood that, if any prior art publication is referred toherein; such reference does not constitute an admission that thepublication forms a part of the common general knowledge in the art inany country. Although the foregoing invention has been described in somedetail by way of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and Examples should not be construed as limiting the scopeof the invention.

What is claimed is:
 1. A compound of formula (I), a stereoisomerthereof, an atropisomer thereof, a pharmaceutically acceptable saltthereof, a pharmaceutically acceptable salt of the stereoisomer thereofor a pharmaceutically acceptable salt of the atropisomer thereof:

Wherein: the

in the formula (I) is selected from:

R₂₁ is selected from halogen; R₂₂ is selected from hydrogen; R₃ isselected from

each hydrogen in the R₃ at each occurrence is independently optionallysubstituted by 1 R₃₁ or 2 R₃₁; Each R₃₁ at each occurrence isindependently selected from —C₁₋₆alkyl; R₄ is selected from

is independently optionally substituted by 1 R₄₂ or 2 R₄₂; R₄₁ isselected from

R_(4a), R_(4b) or R_(4c) is independently selected from hydrogen orhalogen; Each R₄₂ at each occurrence is independently selected from—C₁₋₆alkyl or —C₁₋₆alkylene-CN.
 2. The compound of formula (I), astereoisomer thereof, an atropisomer thereof, a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable salt of thestereoisomer thereof or a pharmaceutically acceptable salt of theatropisomer thereof according to claim 1, wherein: R₂₁ is selected from—F.
 3. The compound of formula (I), a stereoisomer thereof, anatropisomer thereof, a pharmaceutically acceptable salt thereof, apharmaceutically acceptable salt of the stereoisomer thereof or apharmaceutically acceptable salt of the atropisomer thereof according toclaim 1, wherein: R₃ is selected from


4. The compound of formula (I), a stereoisomer thereof, an atropisomerthereof, a pharmaceutically acceptable salt thereof, a pharmaceuticallyacceptable salt of the stereoisomer thereof or a pharmaceuticallyacceptable salt of the atropisomer thereof according to claim 3,wherein: R₃ is selected from


5. The compound of formula (I), the stereoisomer thereof, theatropisomer thereof, the pharmaceutically acceptable salt thereof, thepharmaceutically acceptable salt of the stereoisomer thereof or thepharmaceutically acceptable salt of the atropisomer thereof according toclaim 1, wherein: R₄ is selected from:


6. The compound of formula (I), the stereoisomer thereof, theatropisomer thereof, the pharmaceutically acceptable salt thereof, thepharmaceutically acceptable salt of the stereoisomer thereof or thepharmaceutically acceptable salt of the atropisomer thereof according toclaim 5, wherein: R₄ is selected from:


7. The compound of formula (I), the stereoisomer thereof, theatropisomer thereof, the pharmaceutically acceptable salt thereof, thepharmaceutically acceptable salt of the stereoisomer thereof or thepharmaceutically acceptable salt of the atropisomer thereof according toclaim 6, wherein: R₄ is selected from:


8. The compound of formula (I), the stereoisomer thereof, theatropisomer thereof, the pharmaceutically acceptable salt thereof, thepharmaceutically acceptable salt of the stereoisomer thereof or thepharmaceutically acceptable salt of the atropisomer thereof according toclaim 1, wherein: the compound is selected from:


9. The compound of formula (I), a stereoisomer thereof, an atropisomerthereof, a pharmaceutically acceptable salt thereof, a pharmaceuticallyacceptable salt of the stereoisomer thereof or a pharmaceuticallyacceptable salt of the atropisomer thereof according to claim 1,wherein: the compound is selected from:


10. A pharmaceutical composition comprising the compound of formula (I),a stereoisomer thereof, an atropisomer thereof, a pharmaceuticallyacceptable salt thereof, a pharmaceutically acceptable salt of thestereoisomer thereof or a pharmaceutically acceptable salt of theatropisomer thereof according to claim 1, and at least onepharmaceutically acceptable excipient.